The present invention relates to methods and systems for controlling evaporative drying processes. More particularly, the present invention relates to methods and systems for controlling evaporative drying processes using environmental equivalency.
Evaporative drying processes, such as tablet film coating, spray drying, and fluid bed processing, utilize evaporative drying to achieve a desired output product quality. For example, in tablet film coating, tablets are placed in the coating pan of a tablet coater. The coating pan is a perforated or semi-perforated cylinder, similar in appearance to the tumbler of a conventional clothing dryer. The coating pan rotates as a coating material, such as a solution or a suspension, is sprayed onto the tablets. In order to dry the coating material on the tablets, a heated gas, such as air, is pumped or drawn into the chamber through a gas inlet. The gas evaporates liquid from the coating material and exits through a gas outlet.
Some of the parameters associated wit tablet film coating are:
drying gas temperature;
dew point;
drying gas flow rate;
spray rate; and
solution/dispersion percentage of solids.
In order to achieve proper coating of tablets using conventional methods, optimal values for each of these parameters must be determined empirically. In addition, subsequent processes must be carefully controlled to ensure that the optimal parameter values are maintained.
In order to determine optimal values for tablet film coating parameters, many experiments must be performed. For example, a process technician may start coating tablets in a tablet coater using initial values for the above-listed parameters. The quality of the coating of the tablets may be analyzed to determine required adjustments in the parameters. This process is repeated until optimal values are determined for the parameters. The optimal parameter values are then programmed into a control device, such as a programmable logic controller, to control subsequent coating of tablets.
The empirical method for determining optimal parameter values is undesirable for a variety of reasons. When multiple tests are required in order to determine optimal parameter values, many hours of tablet coater operation are required. As a result, a pharmaceuticals manufacturing company may be required to slow production or purchase multiple tablet coaters in order to maintain a given production level. The increased time and/or equipment required to empirically determine optimal process parameters undesirably increases the cost of developing evaporative drying processes, such as tablet film coating.
Another problem associated with conventional development of evaporative drying processes is that conventional development of evaporative drying processes is product specific. In other words, experimental tests must be performed for each new product to determine optimal process parameters. This testing undesirably increases labor and expense associated with conventional evaporative drying processes.
Another reason that the conventional empirical method of determining optimal process parameter values is undesirable is that results may not be scalable. For example, parameter values determined for a small tablet coater may not be valid for a larger tablet coater and vice versa. As a result, new parameter values may have to be determined when the scale of a process changes. In addition, model parameters that hold true for one processing environment may not be transferrable to another processing environment. For example, parameter values for a tablet film coating process operating in one geographic area with a high relative humidity may not be transferrable to another geographic area with a low relative humidity. As a result, empirical tests must be performed in the new geographic area to determine optimal parameter values for the new area. This lack of scalability and transferability associated with conventional tablet film coating process control results in increased labor and expense.
Still another problem associated with tablet film coating is the time required to start coating tablets. For example, in convention tablet coating minutes or even hours may be required to reach operating parameter values. This increased startup time decreases production for a given tablet coater.
Yet another problem associated with conventional tablet film coating is that when one or more process parameters change during a tablet coating operation, this change may adversely affect output product quality. For example, if inlet air humidity or temperature changes during a tablet coating operation, other parameters may require adjustment during the operation in order to compensate for the changes. Such compensation may require continuous monitoring and manual adjustment by an operator throughout the tablet coating process. Thus, conventional methods for manufacturing pharmaceutical products may be labor-intensive.
xe2x80x9cA Thermodynamic Model for Aqueous Film-Coatingxe2x80x9d, Pharmaceutical Technology, April 1987, by Glenn C. Ebey of Thomas Engineering, describes a dimensionless quantity, referred to as environmental equivalency (EE), that can be used to model relationships between process parameters associated with aqueous film coating. In the publication, an example is given where environmental equivalency is used to determine a new inlet air temperature for a tablet coater to produce a desired environmental equivalency value when inlet air humidity changes. The new inlet air temperature is determined as follows. First, the example states that xe2x80x9ca good quality of coating can be obtained at an inlet air temperature of 149xe2x96xa1F, an air flow rate of 2000 actual cubic feet per minute, a humidity ratio of 25 grains per pound mass, and a spray rate of 400 grams per minute, using a solution of 10% solidsxe2x80x9d. Based on these parameters, an EE value of 2.990 is calculated. The humidity of the processing environment changes to 125 grains per pound mass. The inlet air temperature required to maintain the same EE value is then calculated. In the example, the resulting inlet air temperature is 160xe2x96xa1F in order to achieve the same EE value.
While the publication describes, in theory, a method for modeling film coating processes using environmental equivalency, the example reiterated above only demonstrates how to change one variable associated with a film coating process to compensate for a step change in another variable, while the remaining parameters are held constant. In a real tablet coating system, multiple parameters may change and/or require adjustment during a tablet coating operation. Such multi-variable changes and adjustments are not addressed in the publication.
Another shortcoming of the publication is that a control system for continuously adjusting process parameters to maintain EE values is not disclosed. In the example stated above, when the humidity changes from 25 to 125 grains per pound mass, a new inlet air temperature is calculated such that the EE value will be 2.9. Such calculations may be useful for a step change in humidity, such as that which occurs when a process is moved from one geographical location to another and humidity remains constant at the new location. However, in real systems, process parameters may vary sinusoidally about setpoints, as determined by time constants of the respective control systems for process parameters. Thus, it is desirable in a real system to continuously measure process parameters and use the measured values to maintain a desired EE value.
Yet another shortcoming of the publication is that it does not address preferred ranges of EE values for tablet film coating. Finally, the publication does not address the application of environmental equivalency control to evaporative drying processes other than aqueous tablet film coating, such as spray drying, fluid bed processing, or other evaporative drying processes.
In light of these difficulties, there continues to exist a long-felt need in the pharmaceuticals industry and other industries that utilize evaporative drying for improved methods and systems for controlling processes using environmental equivalency.
According to the present invention, environmental equivalency-based control systems are applied to evaporative drying processes, such as tablet film coating, spray drying, textiles manufacturing, food processing, deposition of materials on substrates in semiconductor manufacturing, painting, chemical and petro-chemical isolation or purification, contaminant removal, and fluid bed processing. Parameters associated with an evaporative drying process are continuously monitored and fed to an environmental equivalency calculator/controller. As used herein, continuously monitoring process parameters refers to sampling process parameters at fixed or variable time intervals during an evaporative drying process. The environmental equivalency calculator/controller calculates an environmental equivalency value for the process and compares the value to a preferred range of values. If the calculated environmental equivalency value is not within the desired range of values, the environmental equivalency calculator/controller calculates a value for one or more parameters associated with the evaporative drying process and applies the new parameter value to the process. In this manner, the environmental equivalency-based control systems according to the present invention are capable of maintaining the environmental equivalency value for a process within a desired range of values. As a result, consistent product quality can be achieved, even when parameters change during the operation being performed. In addition, because control systems that use environmental equivalency are product-independent, the overall efficiency of a process is increased.
Environmental equivalency may also be used in the process transfer of evaporative drying processes, such as tablet coating, fluid bed processing, spray drying, textiles manufacturing, food processing, deposition of materials on substrates in semiconductor manufacturing, painting, chemical and petro-chemical isolation or purification, and contaminant removal. As used herein, the phrase xe2x80x9cprocess transferxe2x80x9d refers to the act of transferring the manufacture of a specific product from one manufacturing system to another, e.g., film coating the same drug product on two different models/sizes of tablet coaters. The EE value is a dimensionless value that is indicative of the rate of the drying process. The EE value can be applied to aqueous or solvent-based processing for the operation at hand. In short, it is used to describe the environmental nature of the process. The environmental nature of a process refers to the relative rates at which heat and mass are transferred into and out of the system. The EE value is computed from an explicit mathematical expression that is a function of process-dependent variables. The expression used to calculate environmental equivalency is derived from first principles utilizing mass and energy balances around the drying system.
Applied to the pharmaceutical industry, environmental equivalency is an extremely valuable tool in process transfer. Evaluation, monitoring, and control of the environmental equivalency factor can be used to directly impact the quality of the drug product being processed. In the development of a given product, the tablet coating process, for example, has an associated EE value. In the event that the tablet coating process were to be scaled-up from pilot to manufacturing level, the EE value should be matched in the larger scale equipment in order to achieve identical product quality. Likewise, this method also applies to scale-down for the production of smaller batches. Process parameters can be varied to maintain a constant EE value. Determining these process parameters in effect establishes the scaled xe2x80x9crecipexe2x80x9d of the product on the specific piece of processing equipment being used.
The formula used to calculate the environmental equivalency value is derived from mass and energy balances of the process streams with application of the first law of thermodynamics to the drying system from a xe2x80x9cblack boxxe2x80x9d approach. The particular model presented here is tailored to aqueous drying processes, such as aqueous tablet film coating. The formula is as follows:   EE  =                    A        H                    A        M              =                            [                                                    Mp                w                                            RT                w                                      -                                          Mp                f                                            RT                f                                              ]                ⁢                  h          ig                            ρ        ⁢                  xe2x80x83                ⁢                              C            p                    ⁡                      (                                          T                f                            -                              T                B                                      )                              
The variables used are defined as follows:
AH=Area of heat transfer
AM=Area of mass transfer
M=Molar weight of water [lbm/lb-mole]
pw=Partial pressure of water vapor at the mass transfer conditions [lbf/ft2]
pf=Partial pressure of water vapor in the free air stream [lbf/ft2]
R=Universal gas constant [lbf-ft/lbm-mole-xc2x0 R]
Tw=Temperature at the mass transfer conditions [xc2x0 R]
Tf=Free air stream temperature [xc2x0 R]
hig=Change in enthalpy of the water [BTU/lbm]
xe2x96xa1=Density of the air stream [lbm/ft3]
CP=Specific heat capacity of air [BTU/lbn-xc2x0 F]
TB=Heat transfer surface temperature [xc2x0 R]
The technical definition of EE is the ratio of the area of heat transfer, AH, to the area of mass transfer, AM. Low EE values, near 1, characterize wet processes. Higher values indicate dryer conditions.
Although the parameters in the equation indicate removal of water from a product in air, the present invention is not limited to removing water from a product in air. For example, according to the present invention, environmental equivalency can also be applied to solvent-based drying processes and processes where drying occurs in gases other than air. For example, for tablet film coating, spray drying, fluid bed processing, or any other evaporative drying process, any of the Noble gases may be used to dry the product. In addition, organic solvents may be used to coat a product. If the solvent and/or the drying gas is modified, the variables in the equation must be changed according to the physical and chemical properties of the solvent and/or drying gas being used. In addition, the preferred range of environmental equivalency values may change for solvents other than water.
Aqueous film coating is a core process critical to tablet dosage form manufacturing. Current methods of coating process transfer are oftentimes ineffective and involve costly multiple experimental trials in order to achieve the desired end product quality. Implementation of the EE model can eliminate these inefficiencies and ensure expedient development of scale-up production recipes.
In the application of environmental equivalency-based control to the tablet coating process, there are both constant and variable factors along with assumptions. The model assumes that the process is adiabatic and thermodynamically ideal. Adiabatic processes are those in which heat transfer to the surroundings is zero. In this case, all of the heat input to the system leaves through the process streams, not to the film coater""s surroundings (the air, walls, etc. around the coater). The model is described as thermodynamically ideal because it uses the basic, fundamental equations for quantifying mass and heat transfer without consideration of non-linear properties of the chemical species involved. These assumptions hold true for the ranges of operating parameters for evaporative drying processes.
Factors and conditions that may not be incorporated in the evaluation of environmental equivalency for tablet film coating are pan speed, nozzle configuration, location of temperature sensors, load size, and tablet geometry. These factors yield insignificant effect upon heat and mass transfer and therefore do not affect the drying process.
The primary variables in aqueous tablet coating that are critical to calculating environmental equivalency values are inlet gas temperature, gas flow rate, humidity, percent solids in the coating solution, and spray rate. Changes in these variables cause changes in the environmental equivalency value. Increasing inlet gas temperature, inlet gas flow rate, and percentage solids cause an increase in the environmental equivalency value, increasing the drying rate. Increases in inlet gas humidity and spray rate cause a decrease in the environmental equivalency value, slowing the drying rate. The present invention includes methods and systems for continuously measuring and adjusting process parameter values to maintain a desired range of environmental equivalency values.
Accordingly, it is an object of the invention to provide methods and systems for controlling evaporative drying processes using environmental equivalency.
It is yet another object of the invention to provide a method for calculating a process control parameter in an environmental-equivalency-based control system.
Some of the objects of the invention having been stated hereinabove, other objects will become evident as the description proceeds, when taken in connection with the accompanying drawings as best described hereinbelow.